This clinical trial examines the use of the memory-enhancingdrug methylene blue (MB) to facilitate prolonged exposure therapy (PE) in the treatment of chronic posttraumatic stress disorder (PTSD). The efficacy of variants of exposure therapy and, in particular, prolonged exposure, has been replicated across studies with men and women who have experienced a wide range of traumatic events (e.g., Institute of Medicine, 2007). Although PE is highly efficacious, approximately 20-30% of treatment completers continue to have a PTSD diagnosis, slightly more (30-40%) fail to achieve a stringent criterion for good end-state functioning (Foa et al., 1999;Rothbaum et al., 2005), and some fail to complete treatment (20.3%, Hembree et al., 2003). Thus, there is room to further improve PTSD treatment outcomes. The memory-enhancing drug methylene blue administered acutely after extinction training improves fear extinction learning in rats (Gonzalez-Lima &Bruchey, 2004;Wrubel et al., 2007). MB is a metabolic enhancer that is thought to stimulate mitochondrial oxidative metabolism (Sakata et al., 2005;Callaway et al., 2004) and is an FDA-grandfathered drug that, when administered orally in low doses, has been used safely and without significant side effects in humans for years (Meissner et al., 2005;Naylor et al., 1986;1987;1988;Peter et al., 2000). Strong animal research, in combination with established safety and pilot data showing MB-enhanced extinction in humans, provides a firm foundation to extend this work to extinction-based therapies for PTSD such as PE. We seek to pursue the next phase of translation, moving fear-based extinction augmentation using methylene blue in rats to clinical practice in humans by conducting a small feasibility trial. Specifically, this clinical trial will examine the initial safety and relative efficacy of methylene blue in comparison to placebo (PBO) in facilitating extinction learning following imaginal exposure for the treatment of chronic PTSD. We will conduct a double-blind randomized feasibility trial. Males and females with chronic PTSD will be randomly assigned to one of three conditions: imaginal exposure plus MB, imaginal exposure plus matched placebo, or waitlist. 260mg MB or PBO will be administered following five daily imaginal exposure sessions. Physiological and subjective arousal and medication side effects will be monitored. Pre-, post-, and brief follow-up changes in PTSD and other trauma-related symptoms will be assessed, including generalization of extinction learning. PUBLIC HEALTH RELEVANCE: This project proposes to use the memory-enhancing drug, methylene blue (MB), to facilitate prolonged exposure therapy for chronic posttraumatic stress disorder (PTSD). MB, if shown to be a useful adjunct to exposure treatments, will render exposure therapy a more cost-efficient treatment by decreasing the number of treatment sessions, promoting a quicker treatment response, reducing treatment dropout, and making treatment gains more durable over time.